Strategies to expand the distribution of nursing talent in the United States.

This panel paper is the third installment in a six-part Nursing Outlook special edition based on the 2022 Emory Business Case for Nursing Summit. The 2022 summit was led by Emory School of Nursing in partnership with Emory School of Business. It convened national nursing, health care, and business leaders to explore possible solutions to nursing workforce crises, including the nursing shortage. Each of the summit's four panels authored a paper in this special edition on their respective topic(s). This panel paper focuses on strategies to optimally distribute nursing talent in rural and underserved areas. It discusses the role of nursing talent distribution in ensuring equity in access to care for U.S. populations. Topics covered include the need for expanded and standardized advanced practice registered nurse (APRN) scope of practice, an expanded nurse licensure compact, reimbursement reforms, and competitive nursing salaries.

Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8.

Bromodomain-containing proteins frequently reside in multisubunit chromatin complexes with tissue or cell state-specific compositions. Recent studies have revealed tumor-specific dependencies on the BAF complex bromodomain subunit BRD9 that are a result of recurrent mutations afflicting the structure and composition of associated complex members. To enable the study of ligand engaged complex assemblies, we established a chemoproteomics approach using a functionalized derivative of the BRD9 ligand BI-9564 as an affinity matrix. Unexpectedly, in addition to known interactions with BRD9 and associated BAF complex proteins, we identify a previously unreported interaction with members of the NuA4 complex through the bromodomain-containing subunit BRD8. We apply this finding, alongside a homology-model-guided design, to develop chemical biology approaches for the study of BRD8 inhibition and to arrive at first-in-class selective and cellularly active probes for BRD8. These tools will empower further pharmacological studies of BRD9 and BRD8 within respective BAF and NuA4 complexes.

A small-molecule inhibitor of C5 complement protein.

The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein.

Structure of lipoprotein lipase in complex with GPIHBP1.

Lipoprotein lipase (LPL) plays a central role in triglyceride (TG) metabolism. By catalyzing the hydrolysis of TGs present in TG-rich lipoproteins (TRLs), LPL facilitates TG utilization and regulates circulating TG and TRL concentrations. Until very recently, structural information for LPL was limited to homology models, presumably due to the propensity of LPL to unfold and aggregate. By coexpressing LPL with a soluble variant of its accessory protein glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) and with its chaperone protein lipase maturation factor 1 (LMF1), we obtained a stable and homogenous LPL/GPIHBP1 complex that was suitable for structure determination. We report here X-ray crystal structures of human LPL in complex with human GPIHBP1 at 2.5-3.0 Å resolution, including a structure with a novel inhibitor bound to LPL. Binding of the inhibitor resulted in ordering of the LPL lid and lipid-binding regions and thus enabled determination of the first crystal structure of LPL that includes these important regions of the protein. It was assumed for many years that LPL was only active as a homodimer. The structures and additional biochemical data reported here are consistent with a new report that LPL, in complex with GPIHBP1, can be active as a monomeric 1:1 complex. The crystal structures illuminate the structural basis for LPL-mediated TRL lipolysis as well as LPL stabilization and transport by GPIHBP1.

Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor.

IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2R alpha, IL-2R beta, and gamma(c). Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 A resolution. The quaternary structure is consistent with a stepwise assembly from IL-2/IL-2R alpha to IL-2/IL-2R alpha/IL-2R beta to IL-2/IL-2R alpha/IL-2R beta/gamma(c). The IL-2R alpha subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2R alpha with IL-2 at the cell surface. Surprisingly, IL-2R alpha makes no contacts with IL-2R beta or gamma(c), and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2R alpha to deliver IL-2 to the signaling complex and act as regulator of signal transduction. Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2R beta and gamma(c) subunits. Helix A of IL-2 wedges tightly between IL-2R beta and gamma(c) to form a three-way junction that coalesces into a composite binding site for the final gamma(c) recruitment. The IL-2/gamma(c) interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes.

Reliability and responsiveness of the lower extremity functional scale and the anterior knee pain scale in patients with anterior knee pain.

STUDY DESIGN: Prospective methodological study of repeated measures using a sample of consecutive patients. OBJECTIVE: To determine the test-retest reliability and responsiveness of the Anterior Knee Pain Scale (AKPS) and the Lower Extremity Functional Scale (LEFS) in patients with anterior knee pain. BACKGROUND: Anterior knee pain is one of the most common orthopedic complaints affecting the knee. Yet there is currently no self-report outcome measure that has well-established reliability and responsiveness, specifically for this population. As a result, clinicians and researchers may be making inappropriate conclusions regarding patient outcomes by using questionnaires that are misleading. METHODS AND MEASURES: This multisite study involved 30 patients from 4 outpatient physical therapy clinics in Dallas, TX (24 women, 6 men; age range, 16-50 years; mean+/-SD age, 35.2+/-9.1 years). Patients receiving physical therapy for a chief complaint of anterior knee pain completed the AKPS and LEFS at their initial appointment and again 2 to 3 days later. Upon completion of physical therapy, the patients completed the AKPS, LEFS, and a global rating of change form. The treating therapist also completed a global rating of change form at the patient's final visit. The mean of the patient's and therapist's global rating of change was used as the criterion measure of change. RESULTS: Test-retest reliability was high for both questionnaires (ICC2,1 = 0.95 for the AKPS and 0.98 for the LEFS). A significant correlation was found between the criterion measure of change and both questionnaires. Receiver-operating characteristic curve analysis revealed that both questionnaires were moderately responsive with the area under the curve slightly higher for the LEFS (0.77) than the AKPS (0.69). CONCLUSION: The LEFS and the AKPS both demonstrated high test-retest reliability and appear to be moderately responsive to clinical change in patients with anterior knee pain. Reliability and responsiveness were slightly higher in the LEFS than the AKPS. Further research is needed to determine if these measures could be modified, or new measures created, to produce an even more sensitive tool for this population.

Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates.

Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent K(i) values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 A with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn(431') in the reaction mechanism along with previously identified key catalytic residues Lys(266) and His(267). Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates.